This invention relates to the field of pharmaceuticals. More specifically, this invention relates to pro-drugs of propofol that are water soluble and non-toxic.
Propofol (2,6-diisopropylphenol) is a low molecular weight phenol that is widely used as an intravenous sedative-hypnotic agent in the induction and maintenance of anesthesia or sedation in humans and animals. Among its advantages as an anesthetic are rapid onset of anesthesia, rapid clearance, and minimal side effects.
Propofol has a broad range of biological and medical applications. For example, it has been reported to be an anti-emetic (Castano et al., Rev. Esp. Anestesiol. Reanim. 42(7):257-60 (1995)), an anti-epileptic (Kuisma M. et al. Epilepsia 36(12):1241-1243 (1995)) and an anti-pruritic. (Borgeat, A. et al., Anesthesiology 80:642-56 (1994); Lawson, S. et al., Brit. J. Anesthesia 64:59-63 (1990).)
Propofol also has significant application as an antioxidant. (Sanchez et al., U.S. Pat. No. 5,308,874; Sanchez et al., U.S. Pat. No. 5,461,080; and Aarts L. et al. FEBS Let. 357(1):83-5 (1995).) In fact, it has been proposed that propofol can replace .alpha.-tocopherol as antioxidant. (Aarts, supra.) Oxidative processes in living materials can result in significant damage. For example, oxidizing agents in the environment, such as smoke or ozone, are inhaled and cause oxidative stress to tissues of the respiratory system. Exposure to sunlight causes damage to skin as a result of chain reactions which originate when the ultraviolet light promotes the production of free radicals, such as superoxide and hydroxyl, within the tissue surface. Other forms of energetic radiation can have the same effect.
Propofol also has been shown to inhibit lipid peroxidation. (Misacchia et al., Pharmacol. Toxicol. (1991) 69:75-77.)
Oxidation also is a component of inflammation. For example, cyclooxygenase oxidizes arachidonic acid into prostaglandins which act as inflammatory mediators. Therefore, inhibiting oxidation is useful in the treatment of conditions with an inflammatory component. In addition, oxidative damage is also caused by other inflammation mediators such as tumor necrosis factor (TNF) and IL-1.
By inhibiting oxidation in tissues of the respiratory tract, propofol is useful in the prophylactic and therapeutic treatment of various pathologic respiratory conditions having an inflammatory component. These include, for example, acid aspiration, adult/infant respiratory distress syndrome, airway obstructive disease, asthma, bronchiolitis, bronchopulmonary dysplasia, cancer, chronic obstructive pulmonary disease ("COPD"), cystic fibrosis, emphysema, HIV-associated lung disease, idiopathic pulmonary fibrosis, immune-complex-mediated lung injury, exposure to an oxidizing agent, ischemia-reperfusion injury, mineral dust pneumoconiosis, drug-induced lung disease and silo-filler's disease.
There is an extensive accumulation of evidence that either the pathogenesis or the subsequent damage pathways in various neurodegenerative diseases involve reactive oxygen species, and are therefore amenable to treatment with antioxidants. (A review of this subject is given by Simonian A. and Coyle J. T., "Oxidative Stress in Neurodegenerative Diseases", in Ann. Rev. Pharmacol. Toxicol. 36:83 (1996).) Examples of specific neurodegenerative diseases where oxidative damage may play a role include Friedrich's disease (Helveston et al., Clinical Neuropharnacology 19(3):271 (1996)), Parkinson's disease (Jenner, Pathologie Biologie 44(1):57 (1996)), Alzheimer's disease (Good et al., Am. J. Pathol. 149(1):21 (1996)), Huntington's disease (Borlongan et al., Journal of the Florida Medical Association 83(5):335 (1996)), amyotrophic lateral sclerosis (ALS) (Cudkowicz, M. et al. "Free-Radical Toxicity in Amyotrophic Lateral Sclerosis," Ch. 16 in Glutathione in the Nervous System, Shaw, Ed. (1998); multiple sclerosis (MS) (Hooper, D. et al. "Uric acid, a natural scavenger of peroxynitrite, in experimental allergic encephalomyelitis and multiple sclerosis," Proc. Natl. Acad. Sci. USA 95:675-680 (1998)); Pick disease (Castellani et al., Brain Research 696(1-2):268 (1995)) and aging itself (Beal, Annals of Neurology 38(3):357 (1995).)
Similarly, the incidence of spinal cord injury in the United States is approximately 10,000 new cases per year. The human and financial costs of such injuries are devastating and therapies for treatment of these injuries are urgently needed. There is an accumulation of evidence that the pathogenesis of spinal cord injury, as well as injury to the brain, also involves reactive oxygen species and is therefore amenable to treatment with antioxidants (Castano et al., Rev. Esp. Anestesiol. Reanim. 42(7):257-60 (1995)). Alpha-tocopherol (vitamin E), a well known antioxidant, has been shown to decrease post-traumatic spinal cord ischemia and to enhance chronic neurological recovery. However, vitamin E is taken up into the central nervous system very slowly, making it an impractical agent for the treatment of acute neural injury.
A disadvantage to the use of propofol is that it is almost completely insoluble in water. Therefore, before it can be used for intravenous applications, such as anesthesia, it must be specially formulated in aqueous media using solubilizers or emulsifiers. The early developmental studies with intravenous propofol were performed with clear formulations containing the solubilizer Cremophor EL.RTM.. Later developmental studies and the current commercial products use an oil-in-water emulsion in which the emulsifier is the lecithin mixture Intralipid.RTM.. The commercial products are sold under various names including Diprivan.RTM., Disoprofol.RTM., Disoprivan.RTM., and Rapinovet.RTM..
Formulations that contain solubilizers or emulsifiers have been fraught with problems. Formulations containing the solubilizer Cremophor EL.RTM. have been reported to cause allergic complications (Briggs et al., Anesthesis 37:1099 (1982)). Stable emulsions are technically difficult to prepare and are consequently more expensive. Microbial growth has sometimes been observed in such emulsions and is believed to be supported by the emulsifier components (McHugh et al., Can. J. Anaesth. 42(9):801-4 (1995)).
Other investigators have sought to overcome the problem of water insolubility by incorporating the propofol within a water-soluble carrier such as a cyclodextrin. Such a molecular complex allows delivery of propofol in a clear water solution and the eventual release of propofol in vivo. Unfortunately, the cyclodextrin complex produced cardiovascular complications in vivo, discouraging further study (Bielen et al., Anesth. Analg. 82(5):920-4 (1996)).
Until now, there has been no pharmaceutical preparation of propofol formulated to deliver its beneficial effects without harmful side effects. Thus, the need exists for a water-soluble, stable, non-toxic pharmaceutical composition which is readily converted to propofol in vivo without the need for additives, solubilizers or emulsifiers.